The object of this proposal is to investigate two functions of the nervous system in metabolism: A) to regulate body adiposity by controlling food intake and B) to respond to stress by changing glucose metabolism. For (A) we propose to test our hypothesis that insulin is a metabolic satiety signal for the regulation of food intake which indicates the size of adipose tissue stores. In dogs we propose to assess insulin uptake and distribution into, and clearance from CSF and its potential transport through brain interstitial fluid. In baboons we propose to assess the role, mechanism, and site(s) of action for CCK as a gut and neural peptide which suppresses single meal food intake. We also propose to evaluate potential interactions between CCK and the brain insulin satiety signal. The contribution of a change in CNS IGF-II or its receptor to the insulin effect will also be studied. Abnormal operation of the insulin related weight regulation system will be assessed in the Zucker fatty rat (fa/fa) by studies of the regulation of insulin uptake and effectiveness of action, in food restricted and adrenalectomized fa/fa and lean controls (Fa/Fa and Fa/fa). The potential contribution of IGF-II and its receptors to this genetic obesity will also be assessed. For (B) we propose to assess the role of hepatic neural innervation alone and in conjunction with pancreatic innervation and the adrenal in the development of endogenous hyperglycemia in the dog during activation of the sympathoadrenal system by nerve stimulation and stress. Studies will compare the ability of different types and severities of stress to activate all or part of this neural system. The relative importance of sympathetic neuropeptides such as galanin, and the amines such as norepinephrine and epinephrine in the hyperglycemia will also be evaluated. These studies are designed to understand the role of the nervous system in body weight regulation and stress hyperglycemia, two important contributors to hyperglycemia in man.